NEUROPEPTIDES--MOLECULAR MECHANISM OF ACTION

D-阿片七肽构效关系研究综述 含有以下成分的激动剂和选择性d-阿片类二、三肽拮抗剂 对DMT-Tic进行了修饰，以提高膜的通透性。介绍 激动剂中的AIB因α-螺旋而增强活性和两亲性 队形。拮抗剂在N-末端和C-末端用 通过以下方式提高生物稳定性的疏水成分 尽管如此，还是消除了环化成二酮基哌嗪 Cyclo(DMT-Tic)具有独特的构象，活性较低 而不是线性分子。与甲基的N-烷基化反应保持高d 亲和力和选择性，而乙基、哌啶、吡咯烷或 吡咯降低了对1-2 nm范围的亲和力，随后降低 选择性。C端改性(甲氧基、肼、甲基胺、 金刚烷胺)通过增强m-亲和力来降低d-选择性，例如 金刚烷胺产生了一种与d-D-高亲和力的多肽 以及m受体和激动剂生物活性。一个互补的系统， 通过代表七肽的七肽来诱导疼痛(伤害性感受) 阿片类药物作用的自然调控系统。结构-活性 研究表明，伤害素(1-13)是生物活性最低的 化合物和各种取代作用影响受体和生物活性。 因此，独特的阿片类激动剂和拮抗剂的组合，以及 伤害素系统的十七肽将使我们能够更好地 了解疼痛的治疗并区分阿片类药物和抗阿片类药物 在临床情况下的功能。

Summary of Work: Structure-activity studies on d-opioid heptapeptide agonists and selective d-opioid di- and tripeptide antagonists containing Dmt-Tic were modified to enhance membrane permeability. Introduction of Aib in agonists amplified activities and amphiphilicity due to a-helical formation. The antagonists were modified at N- and C-termini with hydrophobic constituents that increased biological stability by eliminating cyclization to a diketopiperazines, nonetheless cyclo(Dmt-Tic) exhibited a unique conformation whose activity was less than linear molecules. N-Alkylation with methyl groups retained high d affinity and selectivity, whereas ethyl, piperidine, pyrrolidine, or pyyrole reduced affinity to the 1-2 nM range and subsequently decreased selectivity. C-Terminal modification (methoxy, hydrazide, methyl amide, adamantanyl amide) reduced d-selectivity by enhancing m-affinity, such that adamantanyl amide resulted in a peptide with high affinity for d- and m-receptors and agonist bioactivities. A complementary system that induces pain (nociception) through a heptadecapeptide represents the natural regulatory system on opioid effects. Structure-activity relationships revealed that nociceptin (1-13) is the minimal bioactive compound and various substitutions affected receptor and bioactivities. Thus, a combination of unique opioid agonists and antagonists, and the heptadecapeptide of the nociceptin system would permit us to better understand treatment of pain and differentiate opioid from antiopioid functions in clinical situations.